Among genetic alterations found in human cancer, mutations of a tumor suppressor gene p53 are most prevalently seen, and thus the p53 gene is believed to be one of the most important genes relevant to tumorigenicity in the human body (Hollstein M. et al., Science (Washington DC), 253: 49-53, 1991). The p53 gene functions as a transcription factor (Vogelstein B., et al., Cell, 70: 523-526, 1992), and it has been confirmed that, upon its binding to a specific DNA sequence, p53 can activate various genes, including p21/WAF1, MDM2, GADD45, BAX, cyclin G, IGF-BP3, PCNA, and GML (EI-Deiry, W. S., et al., Cell, 75: 817-825, 1993; Wu X., et al., Genes Dev., 7: 1126-1132, 1993; Kastan M. B., et al., Cell, 71: 587-597, 1992; Miyashita T., et al., Cell, 80: 293-299, 1995; Okamoto K., et al., EMBO. J., 13: 4816-4822, 1994; Buckbinder L., et al., Nature, 377: 646-649, 1995; Morris G. E., et al., Proc. Natl. Acad. Sci. USA, 93: 885-899, 1996; and Furuhata T., et. al., Oncogene, 13: 1965-1970, 1996). Among these genes, p21/WAF1, BAX, and GML are thought to be major factors involving cell cycle arrest and apoptosis mediated through p53, whereas GADD45 plays an important role in DNA repair.
Thus, identification of genes regulated by p53 is vital for understanding biological and physiological functions of p53. Furthermore, identification of p53-target genes and elucidation of their functions are eagerly awaited not only by cancer researchers but also by researchers who hope to develop new methods of diagnosis and treatment of cancer through use of such target genes.
It should be noted that the present inventors have already designed and established a method of finding candidates for p53-target genes in the vicinity of functional p53-binding sites (p53-tagged sites) in the human genome. Using the method, the present inventors have successfully demonstrated isolation of the GML gene, whose expression is believed to be positively correlated with sensitivity to anticancer drugs (Furuhata T., et al., Oncogene, 13: 1965-1970, 1996).
An object of the present invention is to provide the demanded information which is vitally important to the above fields; that is, to provide information which can enable finding and identification of target genes for the tumor suppressor gene p53 (p53-target genes) or p53-inducible genes, i.e. novel human genes whose expressions fall under specific transcriptional regulation by p53.